Enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl) sulfonyl] piperazine

ABSTRACT

Levorotatory and dextrorotatory enantiomers of 1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine of the formula  
                 
 
     their preparation and use for the preparation of substantially optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine, which are themselves valuable intermediate products for the preparation of optically active therapeutic compounds having a very high degree of optical purity.

[0001] The present invention relates to new compounds, the substantiallyoptically pure levorotatory and dextrorotatory enantiomers. of1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineof the formula

[0002] to a process for the preparation of these compounds and to theiruse for the preparation of substantially optically pure levorotatory anddextrorotatory enantiomers of1-[(4-chlorophenyl)phenylmethyl]piperazine. The latter compounds, arevaluable intermediates for the preparation of substantially opticallypure therapeutically active compounds, in the levorotatory anddextrorotatory forms.

[0003] These therapeutically active compounds may be used in thetreatment of asthma, allergies, inflammation and anxiety, and assedative or tranquilizing agents. A property frequently observed withthese compounds is their high degree of peripheral and/or centralantihistaminic activity, as the basis for their use as a drug.

[0004] It is well known that the biological properties of manycompounds, such as for example drugs, hormones, herbicides, insecticidesor sweetening agents, are influenced by stereochemical factors. Theimportance of the relationships between the optical activity and thebiological properties, has been stressed since 1926 (A. R. CUSHNY,Biological Relations of Optically Isomeric Substances, Williams andWilliams Co., Baltimore, 1926). Since that time, many examples aboundwhich have confirmed the now generally accepted principle that a racemiccompound and its levorotatory and dextrorotatory enantiomers should beconsidered as entirely distinct pharmacological entities. The opticalactivity, which is an image of the asymmetrical structure of an organiccompound is one of the important factors which govern thepharmacological activity of this compound and its biological response.Indeed, according as to whether the levorotatory or dextrorotatory formof a drug is used, considerable differences in the properties, such asits transport, its distribution in the organism or its elimination canappear. These properties are decisive for the concentration of the drugin the organism or its exposure time at the site of activity.Furthermore, the pharmacological activity of the two isomers can differconsiderably. For example, one enantiomer may be much more active thanthe other or, in a border-line case, this enantiomer could possess aloneall the pharmacological activity, the other being totally inactive andserving only as a simple diluent. It can also occur that thepharmacological activities of the two isomers are different, whichproduces consequently two compounds having distinct therapeuticproperties. Moreover, the metabolism and the toxicity can be verydifferent from one isomer to another, so much so that one of theoptically active isomers can be more toxic than the other. One of themost striking examples in this field is that of thalidomide, where thetwo enantiomers possess similar hypnotic effects but only the Senantiomer has teratogenic effects.

[0005] Finally, it has also to be added that the optical isomers areuseful as probes which are of uttermost importance in the study ofchemical interactions with physiological mechanisms (for example, theselectivity of binding to a receptor).

[0006] That is the reason why many pharmaceutical laboratories devotemuch time and efforts to isolate or synthesize the enantiomers ofpharmacologically active compounds and to study the therapeuticproperties thereof.

[0007] A process for the preparation of the enantiomers of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic aciddihydrochloride, known as a non-sedative antihistamine drug under thegeneric name of cetirizine, is described in British Patent No.2,225,321. This process is based on the use of levorotatory ordextrorotatory 1-[(4-chlorophenyl)phenylmethyl]piperazine as startingmaterial. In that patent, the enantiomers of1-[(4-chlorophenyl)phenylmethyl]piperazine are obtained by chemicalresolution of the racemic form, using conventional methods, inparticular, by salt formation with a suitably selected optical isomer oftartaric acid.

[0008] The major disadvantages of this process are, on the one hand,that the yield of the resolution step of the racemic1-[(4-chlorophenyl)phenylmethyl]piperazine is extremely low (only 12.7%)and, on the other hand, that the optical purity of the dextrorotatoryand levorotatory enantiomers so obtained is insufficient and does notallow the final product to be prepared With an optical purity greaterthan 95%.

[0009] Consequently, it appears to be very desirable to provide newroutes for preparing the enantiomers of 1-[(4-chlorophenyl)phenylmethyl] piperazine with improved optical purity and in betteryields and, thereby, to provide excellent starting materials to produceoptically active isomers of useful drugs with a very high degree ofoptical purity.

[0010] But, to achieve this object, it is necessary to find precursorshaving already the correct stereochemical configuration and which, onthe one hand, can be themselves prepared-relatively simply andeconomically with satisfactory optical purity, and, on the other hand,which can be converted easily and with high yields into thesubstantially optically pure enantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine.

[0011] We have now discovered a new compound,1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine, the is levorotatory and dextrorotatory forms ofwhich comply perfectly with this object.

[0012] Accordingly, the present invention provides as new compounds, thelevorotatory and dextrorotatory enantiomers of1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl) sulfonyl]piperazineof the formula

[0013] According to the present invention, the enantiomers of thecompound of formula I are advantageously in a substantially opticallypure form.

[0014] In the present specification, by “substantially optically pure”,is meant an optical purity greater than 98% and this optical puritycorresponds to the percent excess of the optically active isomer presentin major amount with respect to the optically active isomer present inminor amount, and determined by high performance liquid phasechromatography (HPLC) on a chiral stationary phase.

[0015] This optical purity can be defined by the equation described onpage 107 of the book of J. MARCH, “Advanced organic Chemistry”, JohnWiley &Sons, Inc., New York, 3^(rd) Edition, 1985:${{Optical}\quad {purity}\quad \left( {{in}\quad \%} \right)} = {\frac{\left\lbrack ( + ) \right\rbrack - \left\lbrack ( - ) \right\rbrack}{\left\lbrack ( + ) \right\rbrack + \left\lbrack ( - ) \right\rbrack} \times 100}$

[0016] Where [(+)]=concentration of the dextrorotatory enantiomer; and

[0017] [(−)]=concentration of the levorotatory enantiomer.

[0018] The present invention further relates to a process for preparingthe levorotatory and dextrorotatory enantiomers of1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineof formula I, which comprises reacting an enantiomer of(4-chlorophenyl)phenylmethylamine of the formula

[0019] with a N,N-diethyl-4-methylbenzenesulfonamide of the formula

[0020] wherein X is a chlorine, bromine or iodine atom or the(4-methylphenyl)sulfonyloxy or methylsulfonyloxy group, in the presenceof 2.2 to 4.4 equivalents of an organic or inorganic base per equivalentof the enantiomer of (4-chlorophenyl)phenylmethylamine and at theboiling point of the reaction mixture.

[0021] Bases suitable for use to prepare compounds of formula I includeorganic bases such as ethyldiisopropylamine, N-ethylmorpholine,2,4,6-trimethylpyridine or triethylamine, preferablyethyldiisopropylamine, and inorganic bases such as sodium carbonate.

[0022] The levorotatory and dextrorotatory enantiomers of(4-chlorophenyl)phenylmethylamine of formula II, used as startingmaterials are known compounds; they can be prepared by chemicalresolution of racemic (4-chlorophenyl)phenylmethylamine by known methodsusing tartaric acid. These enantiomers can be prepared with an opticalpurity of at least 98%.

[0023] The compounds of formula III used as starting materials are alsoknown products which can be easily obtained starting frombis(2-hydroxyethyl)amine and using known methods.

[0024] The present invention further relates to the use of the newlevorotatory and dextrorotatory enantiomers of1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineof formula I, for the preparation of the substantially optically pureenantiomers of 1-[(4-chlorophenyl)phenylmethyl]piperazine of the formula

[0025] According to the present invention, the levorotatory anddextrorotatory enantiomers of the compound of formula IV are prepared bya process, which comprises subjecting an enantiomer of1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineof formula I to hydrolysis with hydrobromic acid, in acetic acid mediumand in the presence of a phenolic compound, preferably 4-hydroxybenzoicacid.

[0026] This hydrolysis is generally carried out at a temperature ofbetween 18 and 100° C., preferably at a temperature of about 25° C.

[0027] The advantages resulting from the use of1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineof formula I, in the form of its levorotatory or dextrorotatoryenantiomers according to the invention, are numerous.

[0028] These advantages appear not only at the level of the route whichleads to the enantiomers of the compound of formula I but also at thelevel of the conversion step of these enantiomers to prepare thesubstantially optically pure enantiomers of1-[(4-chlorophenyl)phenylmethyl]piperazine of formula IV.

[0029] First of all, we have found that the enantiomers of the compoundof formula I, with a 4-methylphenylsulfonyl group on the amine function,were practically the sole capable of being synthesized in a whollysatisfactory manner. Indeed, if, in the preparation of these compounds,it is attempted to replace the N,N-diethyl-4-methylbenzenesulfonamide offormula III by a corresponding compound, in which the4-methylphenylsulfonyl group has been replaced by hydrogen or by anotherprotecting group of the amine function such as for example a carbonyl,alkyl or triphenylmethyl group, an important racemization of thestarting compound of formula II and/or of the compound of formula I, orthe production of many undesirable by-products, is observed during theformation of the enantiomer of the compound of formula I.

[0030] Moreover, the starting materials of formula III, wherein the4-methylphenylsulfonyl group would have been replaced by hydrogen, areknown to be extremely toxic due to the presence of a free amine group(nitrogen mustards).

[0031] However, all of these significant disadvantages can be avoided byusing the N,N-diethyl-4-methylbenzenesulfonamide of formula III, asstarting material. Indeed, the enantiomers of1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineof formula I, according to the invention, are prepared by a processwhich does not cause racemization and provides a high yield, which canreach 89%, and these enantiomers are obtained with an optical puritygreater than 98% which, in many cases, approaches 100%, is usingsulfonated raw materials of relatively low toxicity and much lesshazardous to manipulate. This last point means also a considerableadvantage as regards the industrial application of the process accordingto the invention.

[0032] Moreover, the use of the enantiomers of the compound of formula Iis particularly advantageous for the preparation of the enantiomers of1-[(4-chlorophenyl)phenylmethyl]piperazine of formula IV. Indeed,

[0033] on the one hand, the enantiomers of1-[(4-chlorophenyl)phenylmethyl]piperazine of formula IV are obtainedwith a yield much greater than 80%. This yield is considerably higherthan that achievable using the process described in British patent No.2,225,321;

[0034] on the other hand, since the hydrolysis reaction, leading to theformation of the enantiomers of the compound of formula IV, isnon-racemizing, these enantiomers are obtained with an optical puritywhich is much greater than 95%, even approaching 100%.

[0035] The enantiomers of1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineof formula I, according to the invention, thus, open up a highlyfavorable preparative route to the enantiomers of1-[(4-chlorophenyl)phenylmethyl]piperazines of the formula IV.

[0036] The substantially optically pure levorotatory and dextrorotatoryenantiomers of 1-[(4-chlorophenyl)phenylmethyl)piperazine of formula IV,so prepared, are of interest mainly as precursors in the preparation ofsubstantially optically pure therapeutically active levorotatory anddextrorotatory forms of 1-[(4-chlorophenyl)phenylmethyl]piperazines ofthe formula

[0037] wherein R is a methyl, (3-methylphenyl)methyl,(4-tert-butylphenyl)methyl, 2-(2-hydroxyethoxy)ethyl,2-[2-(2-hydroxyethoxy)ethoxy]ethyl, 2-(carbamoylmethoxy)ethyl,2-(methoxycarbonylmethoxy)ethyl or 2-(carboxymethoxy)ethyl radical.

[0038] These compounds, which are already known in the racemic form,possess valuable pharmacological properties and may be used for thetreatment of asthma, allergies and inflammation or as sedative,tranquilizing or anxiolytic agents.

[0039] The preferred compounds of formula V are the levorotatory anddextrorotatory enantiomers of1-[(4-chlorophenyl)phenylmethyl]-4-methylpiperazine, of1-[(4-chlorophenyl)phenylmethyl]-4-[(3-ismethylphenyl)methyl]piperazine, of1-[(4-tert-butylphenyl)methyl]-4-[(4-chlorophenyl)phenylmethyl]piperazine,of 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy)ethanol,of2-[2-(2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethoxy]ethanol,of2-[2-[(4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide,of methyl2-[(2-[4-[4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate andof 2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]aceticacid and the pharmaceutically acceptable salts of these enantiomers.

[0040] The preparation of these substantially optically pure enantiomerscan be carried out by means of known methods which comprise reacting anenantiomer of the compound of formula IV, while hot, with a halide ofthe formula RX wherein R has the meaning given above and X represents ahalogen atom. The enantiomers of formula V are new compounds, with theexception of the compounds where R is a 2-(carboxymethoxy)ethyl radical,and possess valuable antihistaminic properties; in particular, theyexhibit a very distinct difference in behavior as regards the inhibitionof the histamine H receptor, one of the enantiomers being a competitiveinhibitor and the other a non-competitive inhibitor.

[0041] The pharmacological tests described below demonstrate theseproperties.

[0042] The following Examples illustrate the invention without, however,limiting it. In these Examples, the melting points are determined bydifferential scanning calorimetry (D.S.C.) with a temperature gradientof 20° C./min. The optical purity as defined hereinbefore was determinedby high performance liquid phase chromatography, on a chiral stationaryphase (CHIRALPAK AD column, 250×4.6 mm; eluent: 50:50:0.1 (v/v/v)mixture of hexane-ethanol-diethylamine; pressure 104 bar; temperature 25C.; flow rate 1 ml/min).

EXAMPLE 1 Preparation of the Levorotatory and Dextrorotatory Enantiomersof (4-chlorophenyl)phenylmethylamine of Formula II.

[0043] 1. Levorotatory (−)-(4-chlorophenyl)phenylmethylamine.

[0044] This compound is prepared by resolution of racemic(4-chlorophenyl)phenylmethylamine by means of (+)-tartaric acidaccording to the method described by R. CLEMO et al. (J. Chem. Soc.,(1939), p. 1958-1960).

[0045] 2. Dextrorotatory (+)-(4-chlorophenyl)phenylmethylamine.

[0046] This compound is prepared by resolution of racemic(4-chlorophenyl)phenylmethylamine by means of (−)-tartaric acidaccording to the method described by R. CLEMO et al. (loc.cit.).

[0047] 3. Recovery of the Unrequired Enantiomer of (4-chlorophenyl)phenylmethylamine.

[0048] With the aim of recovering and recycling the unrequitedenantiomer of (4-chlorophenyl)phenylmethylamine, the compound issubjected to a racemization reaction and the resulting racemic(4-chlorophenyl)phenylmethylamine is then subjected to a new step ofresolution by means of an isomer of tartaric acid according to themethod described at point 1 or 2 above.

[0049] 4.35 g (0.02 mole) of dextrorotatory(+)-(4-chlorophenyl)phenylmethylamine, 244 mg (0.002 mole) of2-hydroxybenzaldehyde and 1.1 g (0.02 mole) of sodium methoxide aresuspended in 21.8 ml of methanol. The mixture is heated under reflux forfive and a half hours, then allowed to return to ambient temperature and6.7 ml of concentrated hydrochloric acid are added dropwise to themixture. The methanol is evaporated, the residue taken up in 50 ml ofwater, and a further 25 ml of concentrated hydrochloric acid are addedthereto. After 1 hour, the white. precipitate which forms is filteredoff, washed with water and dried under vacuum at 40° C. 3.7 g of racemic(4-chlorophenyl)phenylmethylamine are obtained. Yield 73%. [α]_(D) ²:0°(c=1, methanol).

EXAMPLE 2 Preparation of N,N-diethyl-4-methylbenzenesulfonamides ofFormula III

[0050] 1.4-methyl-N,N-bis[2-[(4-methylphenyl)sulfonyloxy]ethyl]benzenesulfonamide.

[0051] (formula III, X=(4-methylphenyl)sulfonyloxy).

[0052] This compound is prepared fromN,N-bis(2-hydroxyethyl)-4-methylbenzenesulfonamide according to themethod described by D. H. PEACOCK and U. C. DUITA (J. Chem. Soc., (1934)p. 1303-1305).

[0053] M.P. 75.9° C. Yield: 79.7%.

[0054] 2.4-methyl-N,N-bis[2-(methylsulfonyloxy)ethyl]benzenesulfonamide.

[0055] (formula III, X=methylsulfonyloxy).

[0056] A solution of 11.4 g (0.1 mole) of methanesulfonyl chloride in17.1 ml of dichloromethane is cooled to 5° C. A solution of 13 g (0.05mole) of N,N-bis(2-hydroxyethyl)-4-methylbenzenesulfonamide and 10.1 g(0.1 mole) of triethylamine in 52 ml of dichloromethane is then addeddropwise with stirring. The resulting mixture is allowed to return toambient temperature and stirred for a further 3 hours. The reactionmixture is then extracted three times with 40 ml water. The organicphase is-dried over sodium sulfate, filtered and concentrated in arotating evaporator. The resulting oil is then crystallized fromethanol. 17.8 g of4-methyl-N,N-bis[2-methylsulfonyloxy)ethyl]benzenesulfonamide areobtained.

[0057] M.P.: 64.6° C. Yield: 85.7%.

[0058] 3. N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide.

[0059] (formula III, X=Cl).

[0060] This compound is prepared using the method described by K. A.AL-RASHOOD et al. (Arzneim.-Forsch./Drug Res. 40(II) (1990).,p.1242-1245).

[0061] M.P.: 45.8° C. Yield 69.0%.

[0062] 4. N,N-bis(2-iodoethyl)-4-methylbenzenesulfonamide.

[0063] (formula III, X═I).

[0064] 5.7 g (0.01 mole) of 4-methyl-N,N-bis[2-[(4-methylphenyl)sulfonyloxy]ethyl]benzenesulfonamide (prepared as indicated in 1 above)are dissolved in 57 ml of acetone and 4.5 g (0.03 mole) of sodium iodideare added thereto. The resulting mixture is heated under reflux for 22hours. It is then allowed to cool and the acetone is evaporated off. Thesolid residue is taken up in a mixture of 10 ml of water and 25 ml ofdichloromethane and the two phases are separated. The aqueous phase isextracted with 25 ml of dichloromethane and the organic phases arecombined. The combined organic phase is washed successively with 10 mlof a 10% aqueous solution of sodium thiosulfate and then with 10 ml ofwater. The organic phase is then dried over sodium sulfate, filtered andevaporated. The white solid obtained is dried under vacuum at 25° C. 4.7g of N,N-bis(2-iodoethyl)-4-methylbenzenesulfonamide are obtained.

[0065] M.P. 93.8° C. Yield: 98%.

[0066] 5. N,N-bis(2-bromoethyl)-4-methylbenzenesulfonamide.

[0067] (formula III, X═Br)

[0068] This compound is prepared using the method described at point 4above, is except that sodium bromide is used in place of sodium iodideand the reaction mixture is heated in acetone under reflux for 16 days.

[0069] M.P.:69.2° C. Yield 98.7%.

EXAMPLE 3 Preparation of Enantiomers of1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineof Formula I

[0070] A1. Levorotatory(−)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine.

[0071] 3.4 g (0.0156 mole) of levorotatory(−)-(4-chlorophenyl)phenylmethylamine (prepared in Example 1.1) and 5.1g (0.0172 mole) of N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide(prepared in Example 2.3) in 6 ml (4.4 g or 0.0343 mole) ofethyldiisopropylamine are mixed in a 25 ml round-bottomed flask. Themixture is heated under reflux (127° C.) for 4 hours and then cooled,with stirring, to 86° C. and 13.8 ml of methanol are added at once. Themixture is then cooled in an ice bath and still stirred for 1 hour. Theprecipitate which forms is filtered off, washed with 10 ml of methanoland dried under vacuum at 40° C. The product is recrystallized from a3:1 (v/v) mixture of methanol and acetone. 6 g of levorotatory(−)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineare obtained.

[0072] M.P. 171.1° C. Yield: 87.2%.

[0073] [α]_(D) ²⁵: −40.68° (c=1, toluene)

[0074] Optical purity 100%

[0075] Analysis for C₂₄H₂₅ClN₂O₂S in %: Calc.: C 65.37 H 5.71 N 6.35 Cl8.04 S 7.27 Found: 65.95 5.80 6.60 8.12 7.33

[0076] A2 to A5. Influence of the nature of the base.

[0077] Levorotatory(−)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineis also prepared from N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamideusing the method described at point A1 above, but with various otherbases in place of ethyldiisopropylamine.

[0078] The results obtained are set out in Table I, wherein the firstcolumn indicates the number of the Example, the second column, the baseused, the third column, the amount of base used, expressed inequivalents per equivalent of (−)-(4-chlorophenyl)phenylmethylamine, thefourth column, the time (in hours) during which the reaction mixture iskept under reflux, the fifth column, the yield oflevorotatory.(−)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineobtained and the sixth column, the optical purity of the productobtained, expressed in percent. TABLE I Amount Optical of base TimeYield Purity Example 3 Base (eq.) (hours) (%) (%) A1ethyldiisopropylamine 2.2 4 87.2 ≈100 A2 2,4,6-trimethylpyridine 3.0 1.564.2 ≈100 A3 N-ethylmorpholine 2.2 4 61.2 98.4 A4 triethylamine 3.0 4859.7 ≈100 A5 Na₂CO₃/xylene^((*)) 3.0 28 56.7 ≈100

[0079] From this Table, it can be seen that the nature of the base hasonly a small influence on the optical purity of the product obtained.However, it appears that ethyldiisopropylamine is much more advantageousas regards the yield of the reaction.

[0080] A1 to A9. Influence of the nature of theN,N-diethyl-4-methylbenzenesulfonamide of formula III.

[0081] Levorotatory(−)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineis also prepared using the method described at point A1 above, but theN,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide of formula III (X═Cl)used as starting material is replaced by the corresponding brominated(X═Br), iodinated (X═I), tosylated (X=(4-methylphenyl)sulfonyloxy) ormesylated (X=methylsulfonyloxy) derivative, prepared respectively inExamples 2.5, 2.4, 2.1 and 2.2.

[0082] In Table II,

[0083] the first column gives the number of the Example,

[0084] the second column, the nature of the substituent X in thestarting material of formula III,

[0085] the third column, the amount of the compound of formula III used,expressed in equivalents per equivalent of(−)-(4-chlorophenyl)phenylmethylamine, the fourth column, the time,expressed in hours during which the reaction mixture is kept underreflux,

[0086] the fifth column, the yield of levorotatory(−)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineobtained and the sixth column, the optical purity of the productexpressed in percent. TABLE II Amount Optical Compound of formula III ofIII Time Yield Purity Example 3 Substituent X (eq.) (hours) (%) (%) A1C1 1.1 4 87.2 ≈100 A6 Br 1 1 88.9 ≈100 A7 methylsulfonyloxy 1 2 84.6≈100 A8 I 1 1 84.1 99.4 A9 (4-methylphenyl) 1 1 83.8 ≈100 sulfonyloxy

[0087] From this Table, it can be seen that the nature of the compoundof formula III has only a small influence on the optical purity of theproduct obtained. Moreover, the compound of formula III has only a verysmall influence on the yield of the reaction, although the best yield isobtained using the bromine derivative.

[0088] B. Dextrorotatory(+)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine.

[0089] 57 g (0.2618 mole) of dextrorotatory(+)-(4-chlorophenyl)phenylmethylamine (prepared in Example 1.2) and 86.4g (0.2917 mole) of N,N-bis(2-chloroethyl)-4-methylbenzenesulfonamide(prepared in Example 2.3)-are added to 200 ml (1.15 mole) ofethyldiisopropylamine in a 500 ml three-necked round-bottomed flask. Themixture is heated under reflux for 3 hours, then poured in 400 ml ofmethanol and the mixture is cooled, in an ice bath, and stirred for 1hour. The precipitate which forms is filtered off, washed with methanoland dried under vacuum at 50° C. 88.6 g of dextrorotatory(+)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineare obtained.

[0090] M.P. 173.3° C. Yield: 76.7%.

[0091] [α]_(D) ²⁵: +43.2° (c=0.5, toluene).

[0092] Optical purity: 98.35%.

[0093] Analysis for C₂₄H₂₅ClN₂O₂S in %: Calc.: C 65.38 H 5.71 N 6.35 C8.04 S 7.27 Found: 64.98 5.70 6.40 7.96 7.35

EXAMPLE 4 Preparation of Levorotatory and Dextrorotatory Enantiomers of1-[(4-chlorophenyl)phenylmethyl]piperazine of Formula IV

[0094] 1. Levorotatory (−)-1-[(4-chlorophenyl)phenylmethyl]piperazine.

[0095] 370 g (0.839 mole) of levorotatory(−)-1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazine(prepared in Example 3.A1) and 405 g of 4-hydroxybenzoic acid are addedto 1 liter of a 30% solution of hydrobromic acid in acetic acid. Thesuspension is stirred for 17 hours at 25° C. 2 liters of water are thenadded thereto and the suspension is cooled in an ice bath. Theprecipitate which forms is filtered and washed with 750 ml of water. 2liters of toluene and 0.9 liters of a 50% aqueous solution of sodiumhydroxide are then added to the filtrate. The organic phase is decantedoff and washed with 100 ml of water and then once again with 1 liter ofa saturated aqueous solution of sodium chloride. The organic phase isdried over sodium sulfate, filtered and the solvent evaporated off underreduced pressure. The residue is recrystallized from 600 ml of boilinghexane. The solution is filtered while hot, so as to remove any slightlyinsoluble material and the filtrate is then allowed to crystallize,first at ambient temperature, and then for 24 hours in an ice bath. Thecrystals are filtered off, washed with hexane and dried under vacuum at40° C. 204.15 g of levorotatory(−)-1-[(4-chlorophenyl)phenylmethyl]piperazine are obtained.

[0096] M.P.:90.5° C. Yield: 84.8%.

[0097] [α]_(D) ²⁵: −14.25° (c=1, methanol).

[0098] Optical purity: ≧99.8%.

[0099] Analysis for C₁₇H₁₉ClN₂ in %: Calc.: C 71.19 H 6.68 N 9.77 Cl12.36 Found: 71.19 6.84 9.55 11.48

[0100] 2. Dextrorotatory (+)-1-[(4-chlorophenyl)phenylmethyl]piperazine.

[0101] Dextrorotatory (+)-1-[(4-chlorophenyl)phenylmethyl]piperazine isprepared using the method described at point 1 above, but the startinglevorotatory enantiomer of1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineis replaced by the dextrorotatory enantiomer (prepared in Example 3.B).

[0102] M.P.: 91.5° C. Yield: 97.9%.

[0103] [α]_(D) ²⁵: +14.94° (c=1, methanol).

[0104] Optical purity: 100%.

[0105] Analysis for C₁₇H₁₉ClN₂ in %: Calc.: C 71.19 H 6.68 N 9.77 Cl12.36 Found: 70.90 6.74 9.72 12.23

EXAMPLE 5 Use of the Enantiomers of1-[(4-chlorophenyl)phenylmethyl]piperazine in the Preparation ofTherapeutically Active Compounds of Formula V

[0106] 1. Levorotatory Dihydrochloride of1-[(4-chlorophenyl)phenylmethyl]-4-[(3-methylphenyl)methyl]piperazine.

[0107] A solution containing 10 g (0.0348 mole) of dextrorotatory(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example 4.2)in 100 ml of n-butanol is heated at 50° C. 5.5 ml (0.0417 mole) of1-chloromethyl-3-methylbenzene, 8.9 g (0.0836 mole) of sodium carbonateand 0.5 g (0.0030 mole) of potassium iodide are added thereto and themixture is heated at reflux temperature for 3 hours. The-mixture is thencooled and the solid residues removed by filtration and washed with 200ml of toluene. The organic phases are combined and the solventsevaporated until a residual oil is obtained. The oil is redissolved in500 ml of thanol to which 15 ml of concentrated hydrochloric acid,dissolved in 35 ml of ethanol, are added. This solution is cooled in anice bath, the resulting precipitate filtered off-and the filtrateevaporated. The residue obtained after evaporation and the precipitateare combined and suspended in 100 ml of isopropyl alcohol. Thesuspension is filtered and the solids are washed with a small amount ofisopropyl alcohol and-dried under vacuum at 50° C. 12.7 g of thelevorotatory dihydrochloride of1-[(4-chlorophenyl)phenylmethyl]-4-[(3-methylphenyl)methyl]piperazineare obtained.

[0108] M.P.: 252.3° C. Yield: 78.6%.

[0109] [α]₃₆₅ ²⁵: −27.96° (c=1, methanol).

[0110] Optical purity: 100%.

[0111] Analysis for C₂₅H₂₇ClN₂₀.2HCl in %: Calc.: C 64.73 H 6.30 N 6.04Cl⁻ 15.29 Found: 64.45 6.42 5.93 15.18

[0112] 2. Dextrorotatory Dihydrochloride of1-[(4-chlorophenyl)phenylmethyl]-4-[(3-methylphenyl)methyl]piperazine.

[0113] The procedure described at point 1 above is followed using thelevorotatory 1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared inExample 4.1) in place of the dextrorotatory enantiomer and using thesame quantities of reagents. 13 g of the dextrorotatory dihydrochlorideof 1-[(4-chlorophenyl)phenylmethyl]-4-[(3-methylphenyl)methyl]piperazineare obtained.

[0114] M.P.: 252.9° C. Yield: 80.4%.

[0115] [α]₃₆₅ ²⁵: +27.5° (c.=1, methanol).

[0116] Optical purity: =100%.

[0117] Analysis for C₂₅H₂₇ClN₂₀.2HCl in %: Calc.: C 64.73 H 6.30 N 6.04Cl⁻ 15.29 Found: 64.47 6.32 5.88 15.18

[0118] 3. Levorotatory Dihydrochloride of1-[(4-tert-butylphenyl)methyl]-4-[(4-chlorophenyl)phenylmethyl]piperazine.

[0119] A solution containing 10 g (0.0348 mole) of dextrorotatory(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example 4.2)in 100 ml of n-butanol is heated to 50° C. 7.6 ml (0.0418 mole) of1-chloromethyl-4-tert-butylbenzene, 8.9 g (0.0836 mole) of sodiumcarbonate and 0.5 g (0.0030 mole) of potassium iodide are added theretoand the mixture is heated at reflux temperature for 1 hour. It is thencooled and the solids are removed by filtration and washed with 200 mlof toluene. The organic phases are combined and the solvents evaporateduntil a residual oil is obtained. This oil is redissolved in 300 ml ofacetone, and 15 ml of concentrated hydrochloric acid, dissolved in 35 mlof acetone, are added thereto, followed by a further 200 ml of acetone.The mixture is cooled in an ice bath and the precipitate which forms isfiltered off and dried under vacuum at 50° C. 14.68 g of thelevorotatory dihydrochloride of1-[(4-tert-butylphenyl)methyl]-4-[(4-chlorophenyl)phenylmethyl)piperazineare obtained.

[0120] M.P.: 257.7° C. Yield 83.3%.

[0121] [α]₃₆₅ ²⁵: −13.26°. (c=0.2, methanol).

[0122] Optical purity: =100%.

[0123] Analysis for C₂₈H₃₃ClN₂₀.2HCl in %: Calc.: C 66.47 H 6.97 N 5.54Cl⁻ 14.01 Found: 66.35 7.39 5.45 13.85

[0124] 4. Dextrorotatory Dihydrochloride of1-[(4-tert-butylphenyl)methyl]-4-[(4-chlorophenyl)phenylmethyl]piperazine.

[0125] This compound is prepared by using the method described at point3 above, but starting with 4 g of levorotatory(−)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example4.1). 4.75 g of the dextrorotatory dihydrochloride of1-[(4-tert-butylphenyl)methyl]-4-[(4-chlorophenyl)phenylmethyl]piperazineare obtained.

[0126] M.P.: 273.9° C. Yield: 67.4%.

[0127] [α]₃₆₅ ²⁵: +11.33° (c=0.2, methanol).

[0128] Optical purity: 100%.

[0129] Analysis for C₂₈H₃₃ClN₂₀.2HCl in %: Calc.: C 66.47 H 6.97 N 5.54Cl⁻ 14.01 Found: 66.37 7.16 5.27 13.85

[0130] 5. Levorotatory Dihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethanol.

[0131] A solution containing 10 g (0.0348 mole) of dextrorotatory(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example 4.2)in 100 ml of n-butanol is heated to 50° C. 5 ml (0.0464 mole) of2-(2-chloroethoxy)ethanol, 8.9 g (0.0836 mole) of sodium carbonate and0.5 g (0.0030 mole) of potassium iodide are added thereto and themixture is heated at reflux temperature for 16 hours. A further 2 ml of2-(2-chloroethoxy)ethanol are added and refluxing is continued for afurther 4 hours. The mixture is cooled and filtered and the precipitatewashed with 200 ml of toluene. The organic phases are evaporated untilan oil is obtained and this is dissolved in 100 ml of ethanol. 12 ml ofconcentrated hydrochloric acid, dissolved in 38 ml of ethanol, are addedthereto. The solvent is evaporated and the residue recrystallized fromethanol. The precipitate is filtered off and washed with a small amountof isopropyl alcohol (first crop). The filtrate is evaporated and thesolid residue washed with a small amount of isopropyl alcohol (secondcrop). The two crops are recrystallized together from a 30:1 (v/v)mixture of isopropyl alcohol and methanol. 10.57 g of the levorotatorydihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethanol areobtained.

[0132] M.P.: 229.8° C. Yield 67.8%.

[0133] [α]₃₆₅ ²⁵: −6.07° (c=1, water).

[0134] Optical purity: =100%.

[0135] Analysis for C₂₁H₂₇ClN₂O₂.2HCl in % Calc.: C 56.32 H 6.53 N 6.26Cl⁻ 15.83 Found: 56.32 6.79 6.08 15.63

[0136] 6. Dextrorotatory Dihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl)-1-piperazinyl]ethoxy]ethanol.

[0137] Using the same amounts of reagents as used in the methoddescribed at point 5 above, the dextrorotatory enantiomer is prepared inthe same way, but starting with levorotatory(−)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example4.1). 11.7 g of the dextrorotatory dihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethanol areobtained.

[0138] M.P. 231.3° C. Yield: 70.5%.

[0139] [α]₃₆₅ ²⁵: +5.16° (c=1, water).

[0140] Optical purity: =100%.

[0141] Analysis for C₂₁H₂₇ClN₂O₂.2HCl in % Calc.: C 56.32 H 6.52 N 6.25Cl⁻ 15.83 Found: 55.75 6.54 6.10 15.81

[0142] 7. Levorotatory Dihydrochloride of2-[2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethoxy]ethanol.

[0143] A solution containing 10 g (0.0348 mole) of dextrorotatory(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example 4.2)in 100 ml of n-butanol is heated to 40° C. 6.1 ml (0.0419 mole) of2-[2-(2-chloroethoxy)ethoxy)ethanol, 8.9 g (0.0836 mole) of sodiumcarbonate and 0.5 g (0.0030 mole) of potassium iodide are added thereto.The mixture is heated at reflux temperature for six hours. It is thencooled and the solids are removed by filtration and washed with a smallamount of toluene. The filtrate and the washing solvent are combined andthe solvents evaporated. The residue is taken up in 50 ml of toluenewhich is then evaporated. The residue obtained is taken up again in 100ml of toluene, washed with a 100 ml of water and the organic phaseevaporated. The oil obtained after evaporation is dissolved in 100 ml ofisopropyl alcohol. A solution containing 12 ml of concentratedhydrochloric acid in 38 ml of isopropyl alcohol is added thereto and thesolvent evaporated. The solid residue is taken up in 150 ml of hotisopropyl alcohol, 100 ml of hexane are added and the solution heatedunder reflux. The solution is then cooled in an ice bath, filtered andthe precipitate is washed with 50 ml of a 1:1 (v/v) mixture of isopropylalcohol and hexane and then with 50 ml of hexane. The resulting solidproduct is dried under vacuum at 50° C. 12.2 g of the levorotatorydihydrochloride of2-[2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethoxy]ethanolare obtained.

[0144] M.P.: 198° C. Yield 71.13%.

[0145] [α]₃₆₅ ²⁵: −10.7° (c 1, methanol).

[0146] Optical purity: =100%.

[0147] Analysis for C₂₃H₃₁ClN₂O₃.2HCl in %: Calc.: C 56.16 H 6.76 N 5.69Cl_(tot) 21.62 Found: 56.34 7.00 5.67 21.76

[0148] 8. Dextrorotatory Dihydrochloride of2-[2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethoxy]ethanol.

[0149] Using the same method as described at point 7 above, thedextrorotatory enantiomer is prepared starting from levorotbatory(−)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example4.1).

[0150] M.P.:196.1° C. Yield 73.8%.

[0151] [α]₃₆₅ ³⁶: +8.94° (c=1, methanol).

[0152] Optical purity: =100%.

[0153] Analysis for C₂₃H₃₁ClN₂O₃.2HCl.in %: Calc.: C 56.16 H 6.76 N 5.69Cl_(tot) 21.62 Found: 56.48 6.96 5.65 22.1 

[0154] 9. Levorotatory(−)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide.

[0155] 77 g (0.2685 mole) of levorotatory(−)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example4.1), 40.5 g (0.2932 mole) of 2-(2-chloroethoxy)acetamide, 62.8 g (0.591mole) of sodium carbonate and 2 g (0.0120 mole) of potassium iodide areadded to 700 ml of toluene. The mixture is heated at reflux temperaturefor 24 hours. 10 g of Norit are then added and the mixture is filteredwhile hot through Dicalite. The filtrate is washed with 500 ml of waterand then with 500 ml of a saturated aqueous solution of sodium chloride.The organic phase is separated and dried over 250 g of sodium sulfate.It is then filtered and the solvent is evaporated. The residual oil istaken up in 1500 ml of hot diisopropyl oxide. The solution is heatedunder reflux and allowed to crystallize by cooling in an ice bath. Thecrystals are filtered, washed with a small amount of diisopropyl oxideand dried under vacuum at 40° C. 82.91 g of levorotatory(−)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamideare obtained.

[0156] M.P.: 94.3° C. Yield: 79.6%.

[0157] [α]₃₆₅ ²⁵: =23.5° (c=1, methanol).

[0158] Optical purity: =100%.

[0159] Analysis for C₂₁H₂₆ClN₃O₂ in %: Calc.: C 65.02 H 6.76 N 10.83 Cl9.14 Found: 65.39 6.70 10.99 9.23

[0160] 10. Dextrorotatory(+)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide.

[0161] 15 g (0.0523 mole) of dextrorotatory(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example4.2), 8.3 g (0.0601 mole) of 2-(2-chloroethoxy)acetamide, 12.8 g (0.1203mole) of sodium carbonate and 0.5 g (0.0030 mole) of potassium iodideare added to a mixture of 100 ml of p-xylene and 150 ml of toluene. Themixture is heated at reflux temperature for 17 hours. A small amount ofNorit is added and the mixture is filtered while hot through Dicalite.The residue on the filter is washed with a small amount of toluene andthe filtrate and washing solution are combined. The solvents areevaporated and the residue is taken up in 100 ml of toluene. The organicphase is washed successively with 100 ml of water and twice with 100 mlof a saturated aqueous solution of sodium chloride. The organic phase isseparated off and the solvent evaporated. At this point, the cruderesidue obtained could be purified in a manner similar to that describedat point 9 above, in order to obtain dextrorotatory(+)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamidein the form of the free base. However, if desired, the crude residue mayalso be converted to the corresponding dihydrochloride in the followingmanner the crude residue obtained is taken up in 100 ml of acetone,cooled in an ice bath and 15 ml of concentrated hydrochloric acid areadded dropwise thereto.

[0162] A further 200 ml of acetone are added and the mixture is cooledand stirred on an ice bath for 1 hour. The precipitate is filtered offand dried under vacuum at 50° C. 19 g of the levorotatorydihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamideare obtained.

[0163] M.P.:237.4° C. Yield 78.8%.

[0164] [α]₃₆₅ ²⁵ : −19.64° (c=1, methanol).

[0165] Optical purity: =100%.

[0166] Analysis for C₂₁H₂₆ClN₃O₂.2HCl in %: Calc.: C 54.73 H 6.12 N 9.12Cl_(tot) 23.08 Cl⁻ 15.38 Found: 53.70 6.20 8.91 23.08 15.61

[0167] 11. Levorotatory Dimaleate of Methyl2-[2-(4-[(4-chlorophenyl)phenylmethyl]—1-piperazinyl]ethoxy]acetate.

[0168] 46 g (0.16 mole) of levorotatory(−)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example4.1), 36.6 g (0.24 mole) of methyl (2-chloroethoxy)acetate, 37.3 g (0.35mole) of anhydrous sodium carbonate and 1.05 g (0.0064 mole) ofpotassium iodide are suspended in 46 ml of toluene. The suspension isheated with stirring for 18 hours at reflux temperature, then cooled toambient temperature and filtered. The solids are washed with 100 ml oftoluene and the filtrate and the washing solvent are combined. Thetoluene is evaporated at 50° C. under reduced pressure in a rotatingevaporator. 76 g of a brown oil are obtained and are taken up in 80 mlof dichloromethane. The solution is purified by chromatography (silicacolumn (15 to 40 μm) 1 kg; eluent: pure dichloromethane graduallydiluted with methanol up to a maximum of 2% of methanol (v/v)). 43.5 gof methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate inthe form of an oil are thus obtained. Yield 67.5%.

[0169] This compound can be converted to the corresponding dimaleate inthe following manner: 15 g (0.037 mole) of methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetateprepared above are dissolved in 45 ml of methanol at reflux temperatureand 9 g (0.078 mole) of maleic acid are then added at once ther to. Themixture is maintained at reflux temperature until the maleic acid iscompletely dissolved, then the solution is allowed to return to ambienttemperature, always with stirring. The crystals which form are filteredoff and suspended in 15 ml of methanol. The suspension is stirred for anhour and a half at ambient temperature and then again for an hour and ahalf at 0° C. The crystals are filtered off, washed with 15 ml ofmethanol at 0° C. and dried to constant weight. 19.5 g of thelevorotatory dimaleate of methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate areobtained.

[0170] M.P. 143.5° C. Yield 56%.

[0171] [α]₃₆₅ ²⁵: −10.090 (c 1, methanol).

[0172] Optical purity 100%.

[0173] Analysis for C₂₂H₂₇ClN₂O₃ 2C₄H₄ in %: Calc.: C 56.79 H 5.56 N4.41 Found: 56.81 5.68 4.12

[0174] 12. Dextrorotatory Dimaleate of Methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate.14.3 g (0.05 mole) of-dextrorotatory(+)-1-[(4-chlorophenyl)phenylmethyl]piperazine (prepared in Example4.2), 8.4 g (0.055 mole) of methyl (2-chloroethoxy)acetate, 11.7 g (0.11mole) of anhydrous sodium carbonate and 0.332 g (0.002 mole) ofpotassium iodide are suspended in 14.3 ml of toluene. The suspension isheated with stirring for 17 hours at reflux temperature. A further 1.52g (0.01 mole) of methyl (2-chloroethoxy)acetate are added and thesuspension is further heated with stirring for 3 hours at refluxtemperature, then cooled to ambient temperature and filtered. The solidsare washed with 50 ml of toluene and the filtrate and the washingsolvent are combined. The toluene is evaporated at 50° C. under reducedpressure in a rotating evaporator. 22.8 g of a brown oil are obtainedand are taken up in 45 ml of dichloromethane. The solution is purifiedby chromatography (silica column (15 to 40 μm) 1 kg; eluent: puredichloromethane gradually diluted with methanol up to a maximum of 2% ofmethanol (v/v)). 11.1 g of methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl)-1-piperazinyl]ethoxy]acetate inthe form of an oil are obtained.

[0175] Yield: 55.1%.

[0176] This compound can be converted to the corresponding dimaleate inthe following manner: 8 g (0.0198 mole) of methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetateprepared above are dissolved in 16 ml of methanol at reflux temperatureand 4.85 g (0.0417 mole) of maleic acid are then added at once thereto.The mixture is maintained at reflux temperature until the maleic acid iscompletely dissolved, then the solution is allowed to return to ambienttemperature, always with stirring. The crystals which form are filteredoff and suspended in 16 ml of methanol. The suspension is stirred fortwo hours at ambient temperature. The crystals are filtered off, washedwith 10 ml of methanol and dried to constant weight. 7.3 g of thedextrorotatory dimaleate of methyl2-(2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate areobtained.

[0177] M.P. 143.2° C. Yield: 32%.

[0178] [α]₃₆₅ ²⁵: +9.8° (c=1, methanol).

[0179] Optical purity: 100%.

[0180] Analysis for C₂₂H₂₇ClN₂O₃.2C₄H₄ in %: Calc.: C 56.79 H 5.56 N4.41 Found: 56.71 5.58 4.17

[0181] 13. Levorotatory Dihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic Acid.

[0182] 26 ml of concentrated hydrochloric acid are added dropwise to asuspension of 25.2 g (0.065 mole) of dextrorotatory(+)-2-[2-(4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide(prepared at point 10 above) in 70 ml of water, causing the temperatureof the mixture to rise to 38° C. The mixture is then heated at 50° C.for 17 hours. The reaction mixture is then cooled in an ice bath and thepH brought to a value of between 4 and 5 by addition of a 4N aqueoussolution of-sodium hydroxide. The resulting solution is extractedsuccessively with 100 ml, then twice with 50 ml of dichloromethane. Theorganic phases are combined and dried over magnesium sulfate. They arefiltered and the solvent is evaporated. The residual oil is dissolved in243 ml of acetone and the solution is treated with 3.5 g of Norit andfiltered through Celite, which is then washed with 35 ml of acetone. Thesolution is heated at reflux temperature and 198 ml (0.13 mole) ofconcentrated hydrochloric acid are added dropwise thereto. The mixtureis cooled in an ice bath and allowed to stand for one hour. Theprecipitate which forms is filtered off, washed with 100 ml of acetoneand dried under vacuum at 50° C. 24.1 g of the levorotatorydihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl)ethoxy]acetic acidare obtained.

[0183] M.P.: 229.3° C. Yield: 80.3%.

[0184] [α]_(D) ²⁵: −12.79° (c=1, water).

[0185] Optical purity: =100%.

[0186] Analysis for C₂₁H₂₅ClN₂O₃.2HCl in % Calc.: C 54.61 H 5.90 N 6.07Cl⁻ 15.35 Cl_(tot) 23.03 Found: 54.67 5.91 6.03 15.34 23.28

[0187] 14. Dextrorotatory Dihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic Acid.

[0188] The dextrorotatory dihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acidis prepared according to the method described at point 13 above,starting with 25.2 g (0.065 mole) of levorotatory(−)-2-[2-(4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide(prepared at point 9 above). 25.6 g of the desired product are thusobtained.

[0189] M.P.: 227.9°. Yield: 85.3%.

[0190] [α]₃₆₅ ²⁵: +12.87° (c 1, water).

[0191] Optical purity: 99.87%.

[0192] Analysis for C₂₁H₂₁ClN₂O₃.2HCl %: Calc.: C 54.61 H 5.90 N 6.07Cl⁻ 15.35 Cl_(tot) 23.03 Found: 54.71 5.92 6.04 15.34 23.19

[0193] 15. Dextrorotatory Dihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid.

[0194] 13.75 g (0.00216 mole) of the levorotatory dimaleate of methyl2-(2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl)ethoxy]acetate(prepared at point 11 above) are added with stirring and at ambienttemperature to 54 ml of a 2N aqueous solution of sodium hydroxide. Thereaction mixture is extracted successively with 100 ml and 75 ml ofdiethylether and the organic phases are combined. This organic phase isdried over anhydrous sodium sulfate, filtered and the filtration residueis washed with 50 ml of diethylether. The organic phases are combinedand the diethylether is evaporated. The oil thus obtained (8.4 g) istaken up in 50 ml of ethanol and 1.3 g (0.0229) of solid potassiumhydroxide are added thereto. The mixture is heated for one hour atreflux temperature and then allowed to return to ambient temperature,then filtered and the filtrate is evaporated. The residue is taken up in50 ml of water and concentrated in a rotating evaporator to removeresidual ethanol. 10 ml of water are added to the partially concentratedsolution and the pH of the solution is brought to a value of between 4and 5 by addition of a 10% aqueous solution of hydrochloric acid. Theresulting solution is extracted with 50 ml of dichloromethane, the pH ofthe solution is again brought to a value of between 4 and 5 by additionof a 10% aqueous solution of hydrochloric acid and the solution is onceagain extracted with 50 ml of dichloromethane. The organic phases arecombined and dried over anhydrous magnesium sulfate, filtered and thedichloromethane is evaporated. The viscous oil thus obtained (9.8 g) isdissolved in 68.6 ml of acetone and the slightly cloudy solution istreated with 1 g of activated charcoal and filtered while hot throughdiatomaceous earth. 3.6 ml (0.043 mole) of concentrated hydrochloricacid are added to the hot clear yellow solution thus obtained. Thesuspension is allowed to cool to ambient temperature with stirring andstirring of the suspension is continued for one hour at 0° C. Theprecipitate which forms is filtered off, washed with 50 ml of acetoneand dried under vacuum at 40° C. 6.8 g of the dextrorotatorydihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acidare thus obtained.

[0195] M.P.: 227.8° C. Yield: 70.8%.

[0196] [α]₃₅₆ ²⁵: +13.7° (c=1, water).

[0197] Optical purity 100%.

[0198] Analysis for C₂₁H₂₅ClN₂O₃12HCl in %: Calc.: C 54.61 H 5.90 N 6.07Found: 54.18 6.02 5.68

[0199] The following compounds have been subjected to pharmacologicaltests, the results of which are given hereinafter.

[0200] (−)-1-[(4-chlorophenyl)phenylmethyl]piperazine (compound A,prepared in Example 4.1);

[0201] (+)-1-[(4-chlorophenyl)phenylmethyl]piperazine (compound B,prepared in Example 4.2);

[0202] levorotatory dihydrochloride of1-[(4-chlorophenyl)phenylmethyl]-4-[(3-methylphenyl)methyl]piperazine(compound C, prepared in Example 5.1);

[0203] dextrorotatory dibydrochloride of1-[(4-chlorophenyl)phenylmethyl]-4-[(3-methylphenyl)methyl]piperazine(compound D, prepared in Example 5.2);

[0204] levorotatory dihydrochloride of1-[(4-tert-butylphenyl)methyl]-4-[(4-chlorophenyl)phenylmethyl]piperazine(compound E, prepared in Example 5.3);

[0205] dextrorotatory dihydrochloride of1-[(4-tert-butylphenyl)methyl]-4-[(4-chlorophenyl)phenylmethyl]piperazine(compound F, prepared in Example 5.4);

[0206] levorotatory dihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethanol(compound C, prepared in Example 5.5);

[0207] dextrorotatory dihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethanol(compound H, prepared in Example 5.6);

[0208] levorotatory dihydrochloride of2-(2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethoxy]ethanol(compound I, prepared in Example 5.7);

[0209] dextrorotatory dihydrochloride of2-[2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethoxy]ethanol(compound J, prepared in Example 5.8);

[0210](−)-2-[2-(4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide(compound K, prepared in Example 5.9);

[0211](+)-2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamide(compound L, prepared in Example 5.10);

[0212] levorotatory dimaleate of methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate(compound M, prepared in Example 5.11);

[0213] dextrorotatory dimaleate of methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate(compound N, prepared in Example 5.12);

[0214] levorotatory dihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid(compound O, prepared in Example 5.13) and

[0215] dextrorotatory dihydrochloride of2-(2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetic acid(compound P, prepared in Example 5.14).

[0216] 1. Affinity Towards the Histamine H₁ Receptor.

[0217] The affinity of these compounds towards the rat cortex histamineH₁ receptor has been determined using the method described by M. M.BILLAH et al., J. Pharmacol. Exp. Ther., 252 (3), (1990), 1090-1096.

[0218] These conventional assays involve the competitive binding to thehistamine H₁ receptor of, on the one hand, the compound to be testedand, on the other hand, a radioligand, which in the particular case ofthe histamine H₁ receptor is [³H]mepyramine, known to be a selectiveantagonist of this receptor.

[0219] Displacement curves of the binding of [³H]mepyramine are plottedfor various concentrations of the compounds to be tested ranging from10⁻¹⁰ to 10⁻⁴ mole/l, and for a concentration of 4.5×10⁻⁹ mole/l of[³H]mepyramine (24.8 Ci/mmole, provided by New England Nuclear,Belgium).

[0220] Cerebral cortexes from male Sprague-Dawley rats are homogenizedin 2 ml per cortex of a 20 mM Tris-HCl buffer (pH 7.4) containing 250 mMsucrose. The homogenates are centrifuged at 30,000 g for 30 minutes at4° C. and the centrifugation pellets are resuspended in the same freshbuffer and preserved in liquid nitrogen.

[0221] In order to determine the binding to the H₁ receptor, the samplescontaining 0,5 mg of cortex membrane protein, in 0.5 ml-of 50 mMTris-HCl buffer (pH 7.4) containing 2 mM magnesium chloride, areincubated with [³H]mepyramine and the compound to be tested, at 25° C.for 60 minutes. The bound [³H]mepyramine is separated from the freeradioligand by rapid filtration of the sample through a Whatman GF/Cfilter, previously impregnated for at least 2 hours with a 0.1% solutionof polyethyleneimine, in order to reduce the possibility of non-specificbinding of the radioligand with other proteins. The residue from thefiltration is then washed four times with 2 ml of 50 mM Tris-HCl buffer(pH 7.4) and cooled in an ice bath. The radioactivity thereof is thenmeasured using a β particle Tri-carb 1090 scintillation counter(Camberra-Packard, Belgium). Non-specific binding has been estimated inthe presence of a 10 μM aqueous solution of cetirizine and represents30% of the total binding. The IC₅₀ values of the compounds to be tested(concentrations in mole/l necessary to inhibit binding of theradioligand to the H₁ receptor by 50%) are determined by analysis of thecompetitive binding curves (A. DE LEAN et al., Mol. Pharmacol., 21(1982), 5-16) and their inhibition constants (K_(i)) are calculated bymeans of the CHENG and PRUSOFF equation (Y. C. CHENG and W. H. PRUSOFF,Biochem. Pharmacol., 22 (1973), 3099-3108).

[0222] Table III below gives the values of pK_(i) (cologarithm of K_(i))calculated from K_(i) (mean value±deviation with respect to the mean(n=2)), for the compounds tested. TABLE III Compound pKi C 6.2 ± 0.1 D7.2 ± 0.2 E 5.9 ± 0.2 F 6.2 ± 0.0 G 7.6 ± 0.1 H 8.7 ± 0.0 I 7.1 ± 0.0 J8.6 ± 0.0 K 8.6 ± 0.1 L 6.8 ± 0.1 M 8.5 ± 0.1 N 7.1 ± 0.1 O 7.4 ± 0.0 P8.2 ± 0.0

[0223] From this Table, it can be seen that the compounds of formula Vhave good antihistaminic activity. These results also show that there isa difference, between the pK_(i) values for the two enantiomers of onecompound, which corresponds to a difference in relative affinity (thusin, K_(i)) of a factor of between about 2 and 64 towards the rat cortexH₁ receptor. Such a difference indicates that the enantiomer, which hasthe greatest affinity for this type of receptor (for example compound Jcompared with the other enantiomer I), is to be used specifically as ananxiolytic or tranquilizing agent for the treatment of diseases whichare caused by an excitation of the central nervous system.

[0224] 2. Peripheral Antihistaminic Properties.

[0225] The peripheral antihistaminic properties of the compounds aredetermined by measuring the inhibition of the contraction of theisolated guinea pig trachea, caused by histamine, using the methoddescribed by M. H. AMIRI and G. CABELLA (Anat. Embryol., 178 (1988),389-397).

[0226] Tracheas of Dunkin-Hartley guinea pigs of both sexes (weight:250-500 g) are excised and cut into four fragments of three segments ofcartilage each. These fragments are immersed in a Krebs-Heinseleitsolution at 37° C. containing 10⁻⁷ mole/l of atropine and 10⁻⁵ mole/l ofindomethacin and are stretched with a weight of 1 g. The solution isaerated with a current of oxygen containing 5 t carbon dioxide. Eachchange in tension is recorded with an isometric force indicator K 30(from Hugo Sachs Elektronik) coupled to an amplifier and a Sanborn 7700recorder (from Hewlett Packard). The preparation (i.e. trachea fragment)so obtained is allowed to stabilize for one hour during which the baseline for the tension is readjusted if necessary.

[0227] Each preparation is precontracted by the addition of 10⁻⁴ mole/iof histamine to the medium; the observed contraction is taken as areference (100%). After washing and stabilization, a cumulative curveshowing the effects of histamine, as a function of its concentration(10⁻⁶, 10⁻⁵ and 10⁻⁴ mole/l) is plotted as a control.

[0228] For the same preparation, four further cumulative curves showingthe effects of histamine as a function of its concentration are thenrecorded at four increasing concentrations of each compound to betested.

[0229] The compounds to be tested are incorporated in the medium fiveminutes before the histamine. Between each measurement, the preparationsare washed at least four times with an interval of five minutes betweeneach washing. Each compound is tested on at least 6 trachea fragments.When the last curve is plotted, additional concentrations of 3.2×10³¹ ⁴and 10⁻³ mole/i of histamine are added in order to determine whether theantagonism is competitive or not.

[0230] When non-competitive inhibition is observed, pD₂, is calculated,i.e. the cologarithm of the concentration of the compound tested whichcauses a 50% inhibition of the maximum recorded contraction (J. M. VANROSSUM, Arch. Int. Pharmacodyn., 143 (1963), 299-330). When competitiveinhibition is observed, pA₂ is calculated, i.e. the cologarithm of theconcentration of the compound tested which requires the histamine doseto be doubled in order to obtain the same contraction effect.

[0231] Table IV below gives the pA₂ or pD₂, calculated for the compoundstested (mean value t standard deviation). TABLE IV Compound pA₂ pD₂ A5.7 ± 0.4 — B 5.0 ± 0.1 — G 6.5 ± 0.3 — H — 6.7 ± 0.1 I 6.5 ± 0.4 — J —6.0 ± 0.3 K — 6.3 ± 0.2 L 6.4 ± 0.2 — O 6.6 ± 0.3 — P — 6.3 ± 0.2

[0232] This test reveals a surprising, characteristic for the testedlevorotatory and dextrorotatory enantiomer pairs. With the exception ofthe pair of enantiomers A and B, it is found for all the other pairs,that one enantiomer is a competitive inhibitor, whilst the other is anon-competitive inhibitor. This clearly demonstrates the advantage ofpreparing optically pure derivatives of1-[(4-chlorophenyl)phenylmethyl]-piperazine.

[0233] The advantage of the competitive inhibitors stems from the factthat they have generally a lower affinity towards the rat cortex H₁histamine receptor, which predicts that the anti-allergic properties ofthese compounds are associated, very little or not at all, toundesirable effects on the central nervous system, such as for examplesedation or drowsiness. Non-competitive inhibitors have the advantage ofbeing able to inhibit the effects of histamine, even when the latter ispresent in high local concentrations. They, thus, are better indicatedfor the topical treatment of diseases of the skin or the mucousmembranes.

[0234] 3. Inhibition of the Cutaneous Reaction Induced by Histamine inDogs.

[0235] The dog is considered, among the animal species, to be thespecies having a sensitivity to histamine relatively close to that ofman. Thus, it is considered that the antihistaminic activity of acompound, observed in the dog, is predictive of the activity which wouldbe observed in man.

[0236] In this test, nine Beagle dogs are used, having an average weightof 12.6 kg and of about two years of age and of which the abdomens havebeen-locally shaved. 50 μl of a 0.9% aqueous solution of sodiumchloride, containing 10 μg/ml of histamine, is injected intradermallyinto the shaved area. Simultaneously, a solution of Evans blue dye (60mg/ml in a 0.9% aqueous solution of sodium chloride), is administered byintravenous injection to each dog at a dose of 0.1 ml/kg. An allergicreaction develops at the intradermal injection site and there appears awheal, the area of which is measured exactly 30 minutes after the twoinjections. This area is taken as the reference area (100%).

[0237] The compound to be tested is then administered orally, at a doseof 0.15 mg/kg (0.32×10⁻⁶ mole/kg). 0.5, 1.5, 3, 6, 9., 12, 24 and 32hours after administration of the compound to be tested, new wheals areinduced at different abdominal locations by injecting histamine. Eachtime, the area of the induced wheal is measured 30 minutes after theinjection of histamine.

[0238] The antihistaminic activity of a compound on the cutaneousallergic reaction is determined by measuring the reduction in the areaof the induced wheals, following administration of the compound, withrespect to the area of the reference wheal, and then expressed inpercent.

[0239] Table V below, gives the antihistaminic activity obtained forcompound P.

[0240] In this table, the first column indicates the time, expressed inhours elapsed since administration of the tested compound;

[0241] the second column, the area, expressed in mm², of the whealsinduced by histamine (mean observed for nine dogs t standard deviation);

[0242] the third column, the reduction (in percent) in the area-of thewheals observed with time, with respect to the reference area and;

[0243] the fourth column, the statistical significance of the effectobserved with time, evaluated by means of the Wilcoxon test. TABLE VTime Area of wheals Reduction in area Statistical (hours) (mm²) (%)value 0 76 ± 8  100 0.5 65 ± 10 85 p ≦ 0.01  1.5 44 ± 12 58 p ≦ 0.001 333 ± 10 43 p ≦ 0.001 6 41 ± 13 54 p ≦ 0.001 9 41 ± 10 54 p ≦ 0.001 12 41± 10 54 p ≦ 0.001 24 45 ± 5  59 p ≦ 0.001 32 51 ± 5  67 p ≦ 0.01 

[0244] It can be seen that the reduction in the area of the wheals,observed 30 minutes after administration of compound P, is 15%. Maximuminhibition is observed after three hours and reaches 57%. After 32hours, a statistically significant inhibition of 33% is still observed.

[0245] 4. Toxicity.

[0246] The compounds of formula V have low toxicity. The lethal dose(causing death in 2 out of 3 mice following intraperitoneal injection ofthe compounds) is appreciably higher than the dose required to inhibitthe cutaneous reaction induced by histamine in the dog. Table VI givesthe values for the lethal doses (in mice) for the compounds of formulaV. TABLE VI Compound Lethal dose (mole/kg) C >1 × 10⁻³  D >1 × 10⁻³  E 1× 10⁻³ F >1 × 10⁻³  G 6 × 10⁻⁴ H 6 × 10⁻⁴ I 1 × 10⁻⁴ J 1 × 10⁻⁴ K 3 ×10⁻⁴ L 1 × 10⁻³ O 3 × 10⁻⁴ P 3 × 10⁻⁴

[0247] 5. Posology and Administration.

[0248] The compounds of formula V have, in particular, antiallergic andantihistaminic activity as well as tranquilizing and anxiolyticactivity. Pharmaceutical compositions containing these compounds may beadministered orally, parenterally or rectally. They may also beadministered in a nasal spray or instillations (aerosols) or in the formof a cream or ointment.

[0249] For oral administration, solid or liquid forms are used such astablets, gelatine capsules, sugar-coated pills, granulated materials,solutions, syrups, etc.

[0250] For parenteral administration, aqueous or oily solutions,suspensions or emulsions can be suitable.

[0251] For rectal administration, suppositories are used.

[0252] The pharmaceutical forms listed above are prepared using methodscurrently used by pharmacists and can contain traditional excipients inpharmaceutically non-toxic amounts, such as dispersants, stabilizers,preservative agents, sweeteners, coloring agents and the like.

[0253] The percentage of active compound can vary within wide limits,depending upon the mode of administration and in particular thefrequency of administration. As regards the daily dosage, this can varywithin a wide range of from 0.5 to 100 mg, preferably between 2 and 20mg of active compound per day.

We claim:
 1. The levorotatory and dextrorotatory enantiomers of1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineof the formula


2. A process for the preparation of the levorotatory and dextrorotatoryenantiomers of1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineof formula I according to claim 1, which comprises reacting anenantiomer of (4-chlorophenyl)phenylmethylamine of the formula

with an N,N-diethyl-4-methylbenzenesulfonamide of the formula

wherein X is a chlorine, bromine or iodine atom, or the(4-methylphenyl)sulfonyloxy or methylsulfonyloxy group, in the presence2.2 to 4.4 equivalents of an organic or inorganic base per equivalent ofthe enantiomer of (4-chlorophenyl)phenylmethylamine and at the boilingpoint of the reaction mixture.
 3. A process as claimed in claim 2,wherein the base is selected from the group consisting ofethyldiisopropylamine, N-ethylmorpholine, 2,4,6-trimethylpyridine,triethylamine and an alkali metal carbonate.
 4. A process as claimed inclaim 2, wherein the base is ethyldiisopropylamine.*
 5. A process forthe preparation of the levorotatory and dextrorotatory enantiomers of1-[(4-chlorophenyl)phenylmethyl]piperazine of the formula

which comprises subjecting an enantiomer of1-[(4-chlorophenyl)phenylmethyl]-4-[(4-methylphenyl)sulfonyl]piperazineof the formula

to hydrolysis with hydrobromic acid, in acetic acid medium, in thepresence of a phenolic compound, and at a temperature of between 18 and100° C.
 6. A process as claimed in claim 5, wherein the phenoliccompound is 4-hydroxybenzoic acid.
 7. A process for the preparation ofthe levorotatory and dextrorotatory enantiomers of a1-[(4-chlorophenyl)phenylmethyl]piperazine of the formula

wherein R is a methyl, (3-methylphenyl)m thyl,(4-tert-butylphenyl)methyl, 2-(2-hydroxyethoxy)ethyl,2-[2-(2-hydroxyethoxy)ethoxy]ethyl, 2-carbamoylmethoxy)ethyl,2-(methoxycarbonylmethoxy)ethyl or 2-(carboxymethoxy)ethyl radical,which comprises reacting an enantiomer of1-[(4-chlorophenyl)phenylmethyl]piperazine of the formula

while hot, with a halide of the formula RX wherein R has the meaninggiven above and X represents a halogen atom.
 8. A compound selected fromthe group consisting of the levorotatory dihydrochloride of1-[(4-chlorophenyl)phenylmethyl]-4[(3-methylphenyl)methyl]piperazine;the dextrorotatory dihydrochloride of1-[(4-chlorophenyl)phenylmethyl]-4-[(3-methylphenyl)methyl]piperazine;the levorotatory dihydrochloride of 1-[(4-tert-butylphenyl)methyl]-4[(4chlorophenyl)phenylmethyl]piperazine: the dextrorotatory dihydrochlorideof1-[(4-tert-butylphenyl)methyl]-4[(4-chlorophenyl)phenylmethyl]piperazine;the levorotatory dihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy)ethanol; thedextrorotatory dihydrochloride of2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]ethanol; thelevorotatory dihydrochloride of2-[2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy)ethoxy]ethanol;the dextrorotatory dihydrochloride of2-[2-[2-[4-[(4-chlorophenyl)phenylmethyl)-1-piperazinyl)ethoxy]ethoxy]ethanol;the levorotatory2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetamideand its dextrorotatory dihydrochloride; the dextrorotatory2-[2-[4-[(4-chlorophenyl)phenylmethyl)-1-piperazinyl]ethoxy]acetamideand its levorotatory dihydrochloride; the levorotatory dimaleate ofmethyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate) andthe dextrorotatory dimaleate of methyl2-[2-[4-[(4-chlorophenyl)phenylmethyl]-1-piperazinyl]ethoxy]acetate.